Process for the production of dinitrate esters

ABSTRACT

1,2 and 1,3-dinitrate esters are prepared from polyols containing 1,2- or 1,3-diol fragments using an alkyl or aryl boronic acid to form a cyclic boronate ester derivative which is then reacted with dinitrogen pentoxide to directly generate the dinitrate ester. In the cyclic ester from the 1,2- or 1,3-hydroxyl groups are protected and other reactions may then be carried out on other parts of the molecule of which the fragment form a part, leaving the dinitrate ester to be produced subsequently in the final step. High yields are obtained at both stages.

This application is a 371 of PCT/GB 97/02324.

The present invention relates to a method of nitrating polyols havingeither 1,2- or 1,3-diol fragments, which process involves, as anintermediate stage, the use of a 1,3-dioxa-2-borole (boronate ester)protecting group.

A particular problem arises in attempting the nitration of polyolshaving such diol fragments when they are incorporated into a polymericchain. Polyols, even when not of high molecular weight dissolve at bestonly in low concentrations in either water or common organic solventsand in consequence they are difficult to completely nitrate using thecommon mixed acid (sulphuric/nitric acid mixture) or like methods. Evenwhere it is possible to dissolve some of a polymeric polyol into anappropriate solvent the yields of nitrated product obtained are likelyto be very low.

A further problem with conventional nitrating procedures based on mixedacids is that they are rather aggressive in character and tend to besomewhat non-specific. There is thus a considerable possibility whendealing with polymeric polyols that attack by the nitrating agent atsome other location on the polymer chain will occur.

Protection of the reactive hydroxyl groups of 1,2- and 1,3-diolfragments as a cyclic phenyl boronate is well known. The procedure isshown below for a 1,2-diol which will be used hereafter in thedescription of the invention as a general term intended to cover thegroup of polyols containing either 1,2- or 1,3-diol fragments: ##STR1##where n is 0 or 1.

Conventionally, to then obtain the dinitrate ester from the protecteddiol the protecting group is hydrolytically cleaved to recreate the dioland this is then treated with a conventional nitrating agent, with thedisadvantages identified previously.

The applicant has now found that by use of the unconventional nitratingagent dinitrogen pentoxide it is not only possible to achieve nitrationin a relatively non-aggressive manner but also without isolation of thediol. Thus it has been found possible to achieve direct nitrationeffectively and in good yield from a protected diol by treatment withdinitrogen pentoxide.

Accordingly the present invention provides a process for the preparationof 1,2- and 1,3-dinitrate esters from the corresponding polyol having a1,2- or 1,3-diol fragment which comprises the steps of:

a) preparing a cyclic boronate ester derivative of the polyol bytreatment of the polyol with an alkyl or aryl boronic acid;

b) reacting the cyclic boronate ester derivative with dinitrogenpentoxide under anhydrous conditions in order to form the correspondingdinitrate; and

c) separating the dinitrate ester product from the boron-containing sideproduct.

Step (a) of the process may be carried out at any suitable temperaturehaving regard to the stability of the reactants; however the reactionwill generally proceed satisfactorily at or not greatly in excess ofambient temperature. The reaction may most conveniently be carried outby mixing equimolar amounts of the diol with the boronic acid andstirring until the formation of water is evident as a separate layer.Extraction and distillation affords the boronate in excellent yield.

In an optional step between steps (a) and (b), the diol may be modifiedin some other reaction during which the protected hydroxyl groups areunaffected. For example a triol of general formula HO(CH₂)_(n) CHOHCH₂OH can have the 1,2-diol fragment protected as a cyclic boronate and thefree hydroxyl group can be protected as a silyl ether or as an estersuch as an acetate. This gives different protecting groups for thedifferent hydroxyl groups and thus different reactivity and theopportunity for selective deprotection.

It will be appreciated that by avoiding the presence of water, cleavageof the protecting groups and creation of the relatively insolublehydroxyl-bearing compounds is obviated. Thus, provided that other groupssensitive to N₂ O₅ are not present in the protected diol, the problemsof unwanted side reactions and of the lack of solubility of the diols incommon organic solvents are side-stepped. Furthermore the nitratingprocedure according to the present invention requires only a single stepwhereas conventional methods require two steps.

The corresponding cyclic boronate esters are readily obtained from a1,2- or 1,3-diol by reacting the diol with a boronic acid such as analkyl or an aryl boronic acid. Use of the former is preferred, however,because of the tendency of the aromatic ring to be substituted withnitro-groups when the corresponding aryl cyclic esters are nitratedusing N₂ O₅. To achieve nitration of the diol in such cases, therefore,it is necessary to add an excess of the N₂ O₅ reagent to allow for thepreferential nitration of the aromatic ring. The reactions to yieldcyclic boronate esters are found to proceed very efficiently in allcases attempted and the yields are in the range of 80 to 95%. The cyclicboronate esters are found to be stable in air with no evidence ofdecomposition to the boronic acid even after prolonged exposure.

Most conveniently the anhydrous N₂ O₅ reagent used in the process of thepresent invention is a solution of N₂ O₅ in an organic solvent such asdichloromethane. Such a solution may conveniently be prepared asdescribed in UK Patent No. 2,252,309 granted to the present applicant.Using this solution the applicant has found that the combineddeprotection and nitrating reaction will proceed quite rapidly at atemperature of as low as -10° C. Typically reaction temperatures in therange of -30° C. to +25° C. may be utilised and the reaction willproceed to completion in the order of from 0.5 hr to 3 hrs though itwill be appreciated that a combination of reaction temperature and timewhich is appropriate to the stability of the reactants must be employed.However, since N₂ O₅ is itself increasingly unstable in solution attemperatures above about +30° C., it will be understood that atemperature of this order forms a practical upper limit.

The use of such a mild and specific nitration procedure is extremelyadvantageous since it will permit the nitration of diols which might,under more conventional nitrating procedures, undergo attack at otherportions of the diol molecule. Thus, subject only to the absence of anygroup which is susceptible to attack by the N₂ O₅ reagent at therelatively low temperatures required and provided that the protecteddiol is soluble in the solvent chosen, a very wide range of 1,2- and1,3-diols may be nitrated by the process of this invention.

It is desirable that the boronic acid starting material is recovered ina final step of the process because this material will often constituteone of the most expensive reagents for the process and is thereforeadvantageously recycled.

The nitrated products of polymeric diols are energetic materials whichhave important applications in the fields of explosives and propellantseither directly or as precursors for such materials.

The present invention will now be further described with reference tothe following examples.

REACTION PROTOCOL

1. Esterification

The reaction involved in this step may be generally represented asfollows: ##STR2## where R¹ is a butyl or a phenyl group and X is one ofthe following substituents: (CH₂)_(n) OH (a); (CH₂)_(n) OCOCH₃ (b);(CH₂)_(n) OCOPh (c); (CH₂)_(n) CH₃ (d); (CH₂)_(n) Ph (e); (CH₂)_(n)OSi(Me)₂ Bu^(t) (f) or (CH₂)_(n) OSiPr₃ (g) and where n is 2, 4 or 6.

Typically, either butyl or phenyl boronic acid is added to an equimolaramount of the diol or triol. As an example, in the esterification of1,2,6-trihydroxyhexane (compound IIa, n=4) with n-butyl boronic acid(compound I, R¹ =n-butyl), a dry single necked 250 ml round bottomedflask was charged with n-butyl boronic acid (10.2 g, 100 mmol) and1,2,6-trihydroxyhexane (14.1 g, 105 mmol). The flask was flushed withargon before sealing with a rubber septum. Dry diethyl ether (110 ml)was added and the reaction stirred at room temperature. The reaction wasfound to go to completion after 3-4 hrs when the foundation of watercould be observed as a separate layer. At this point an equal quantityof pentane (110 ml) was added followed by a quantity of magnesiumsulphate sufficient to mop up all of the water. The cyclic boronateester product was isolated by simply filtering the solution, evaporatingoff the solvent and distilling the product under reduced pressure togive 18.6 g, 93% yield of the pure cyclic boronate ester (compound IIIa,n=4).

A number of such preparations was carried out. The yields obtained foreach product are set out in Table 1 below and are seen to beconsistently high. The products were found to be analytically pure andno evidence of polymerisation was found when using the triol (productIIIa).

Similarly the esterification reaction of 1,3-diols was also investigatedwith n-butyl boronic acid; a typical example of2-butyl-2-ethyl-1,3-propanediol (compound IVn) is described. The generalreaction procedure is illustrated below: ##STR3## where R¹ is a butyl orphenyl group and the other substituents are selected as follows: X¹ ═X²═Y═Y¹ ═Z═H (h); X¹ ═CH₃, X² ═Y═Y¹ ═Z═H (i); X¹ ═CH₃, X² ═Y═Y¹ ═H, Z═CH₃(j); X¹ ═X² ═CH₃, Y═Y¹ ═H, Z═CH₃ (K); X¹ ═X² ═H, Y═Y¹ ═CH₃, Z═(CH₃)₂ CH(l); X¹ ═X² ═H, Y═CH₂ CH₂ CH₃, Y¹ ═CH₃, Z═H (m); X¹ ═X² ═H, Y═CH₂ CH₂CH₂ CH₃, Y¹ ═CH₂ CH₃, Z═H (n); X¹ ═X² ═H, Y═CH₂ CH₃, Y¹ CH₃, Z═H (o);and X¹ ═X₂ ═H, Y═CH₂ CH₂ CH₃, Y¹ ═CH₂ CH₃, Z═H (p).

A dry single necked 50 ml round bottomed flask was charged with n-butylboronic acid (10 ml of 1.0 M soln. in ether, 10 mmol) and2-butyl-2-ethyl-1,3-propanediol ((IVn); 12 ml of 1.0 M soln. in ether,12 mmol). The flask was flushed with argon before sealing with a rubberseptum. The reaction was found to go to completion after 3-4 hrs whenthe formation of water could be observed as a separate layer. At thispoint an equal amount of pentane (20 ml) was added followed by aquantity of magnesium sulphate sufficient to mop up all of the water.The boronic ester product was isolated by simply filtering the solution,evaporating off the solvent and distilling the product under reducedpressure to give 2.24 g, 98% yield of the pure cyclic boronic ester Vn.The yields obtained for various 1,3-diols are shown below in Table 2.

2. Nitration

A typical example using compound IIIb (n=2; R¹ =butyl) is as follows.

To a 500 ml nitrogen flushed dry 3-necked round bottomed flask fittedwith an alcohol thermometer and magnetic stirrer and dropping funnel wasadded a solution of N₂ O₅ (36.7 g, 0.34 mol) in dichloromethane (250 ml), previously prepared from N₂ O₄ and O₃ at -20° C. All outlets weresealed with rubber septa. 18.2 g, 85 mmol of the cyclic boronate ester(compound IIIb (n=2)) prepared in the manner described above wasintroduced as a solution in dry dichioromethane (50 ml) via the droppingfunnel over 10 mins. between -10 to -20° C. After the addition themixture was allowed to stir for 3-4 hrs between -5 to -20° C. undernitrogen before quenching the reaction by the addition of a saturatedsolution of sodium bicarbonate (3×150 ml). Separation of the layers,drying of the dichloromethane layer with magnesium sulphate, filtrationand removal of the solvent gave 31.1 g of crude compound VIb (n=2) (seebelow). The crude mixture was purified by flash chromatography through asilica column using a gradient eluent system starting off at 100%petroleum ether (40-60° C.) and gradually increasing to 100%dichloromethane to give 17.28 g, 85% yield of pure compound VIb (n=2).Note that due to the explosive nature of nitrate esters distillation ofthe products is not recommended.

Similar nitration procedures can be carried out on the protected 1,3diols (V). A typical nitration of a protected 1,3-diol e.g.2-ethyl-2-butyl-1,3-propanediol (Vn) is as follows.

To a 200 ml nitrogen flushed dry 3-necked round bottomed flask fittedwith an alcohol thermometer and magnetic stirrer and dropping funnel wasadded a solution of N₂ O₅ (0.96 g, 8.94 mmol) in dichloromethane (100ml), previously prepared from N₂ O₄ and O₃ at -20° C. All outlets weresealed with rubber septa. 0.51 g, 2.23 mmol of the cyclic boronic esterVn, prepared as described above was introduced as a solution in drydichloromethane (50 ml) via the dropping funnel over 10 mins. between-10 to -20° C. After addition the mixture was allowed to stir for 3-4hrs between -5 to -10° C. under nitrogen before quenching the reactionby the addition of a saturated solution of sodium bicarbonate (3×50 ml).Separation of the layers, drying of the dichloromethane with magnesiumsulphate, filtration and removal of the solvent gave 0.71 g of crudeVIIn. The crude mixture was purified by flash chromatography through asilica column using a gradient eluent system of 100% petroleum ether(40-60° C.) to 100% dichloromethane to give 0.51 g, 89% yield of pureVIIn. The results for the various protected 1,3-diols are shown in Table2 below.

Although the nitration can be carried out between -20° C. to +30° C. theideal temperature is that used above mainly due to the instability of N₂O₅ at higher temperatures. The acetyl group in compound IIIb (n=2) doesnot undergo nitration under normal conditions. However reactions carriedout where the mixture is allowed to warm up to ambient temperatureduring the course of the reaction were found to contain appreciableamounts of trinitrate ester (compound VI where X represents the group(CH₂)₂ ONO₂). At higher temperatures decomposition of N₂ O₅ to nitricacid occurs readily in solution to give a mixture of N₂ O₅ and nitricacid which is a more powerful nitrating agent than N₂ O₅ alone. Acetylgroups are readily nitrated in this medium, hence the presence of thetrinitrate ester. Under normal nitrating conditions 1.5 equivalents ofN₂ O₅ are sufficient per mole of substrate, however in some of the abovecases 2 equivalents of N₂ O₅ gave better yields. When the ester was aphenylboronic ester three equivalents of N₂ O₅ were used to allow forpreferential nitration of the aromatic ring.

The reaction process for nitration of cyclic boronic esters derived from1,2- and 1,3-diols ay be represented by the following respectiveequations: ##STR4## where R¹ is n-butyl or is phenyl and X representsone of the following substituents: (CH₂)_(n) OH (a); (CH₂)_(n) OCOCH₃(b); (CH₂)_(n) OCOPh (c); (CH₂)_(n) CH₃ (d); (CH₂)_(n) Ph (e); (CH₂)_(n)OSi(Me)₂ Bu^(t) (f) and (CH₂)_(n) OSiPr₃ (g) and n is 2,4 or 6; andwhere X¹ ═X² ═Y═Y¹ ═Z═H (h); X¹ ═CH₃, X² ═Y═Y¹ ═Z═H (i); X¹ ═CH₃, X₂═Y═Y¹ ═H, Z═CH₃ (j); X¹ ═X² ═CH₃, Y═Y¹ ═H, Z═CH₃ (k); X¹ ═X² ═H, Y═Y¹═CH₃, Z═(CH³)₂ CH (l); X¹ ═X² ═H, Y═CH₂ CH₂ CH₃, Y¹ ═CH₃, Z═H (m); X¹═X² ═H, Y═CH₂ CH₂ CH₃, Y¹ ═CH₂ CH₃, Z═H (n); X¹ ═X² ═H, Y═CH₂ CH₃, Z═H,(o); or X¹ ═X² ═H, Y═CH₂ CH₂ CH₃, Y¹ ═CH₂ CH₃, Z═H (p).

The yields obtained for a series of products of formula VI are set outtable 1 below and it can be seen that they are high with the exceptionof silyl derivatives. Examination of the products of nitration in thiscase suggested that rather than producing a nitrated diol or triol,cleavage of the silyl moiety of the cyclic boronate ester had occurred.

The yields obtained for a series of products of formula VII are set outin Table 2 below and it can be seen that they are all high. The startingmaterials in each of these cases are alkyl substituted but analogy withthe functional compounds used for the reactions with 1,2-diols indicatesthat the same functional group tolerance will be observed.

Where R¹ is phenyl as explained earlier it is necessary to use athree-fold amount of N₂ O₅ since two equivalents are preferentially usedup in the nitration of the aromatic ring before nitration of the cyclicboronic ester takes place. Likewise, where the side chain X contained anaromatic ring as with compound III(e), a further two-fold excess of N₂O₅ is required to compensate for preferential attack on the aromaticring in the side chain. In the case of the triol III(a), one furtherequivalent of N₂ O₅ was needed to effect nitration of all of thehydroxyl groups. Good yields of the trinitrate ester were then howeverobtained.

RESULTS

Yields obtained in various preparations are set out in Tables 1 and 2below.

                  TABLE 1                                                         ______________________________________                                                                  isolated yield of                                                                       isolated yield of                                       diol or     purified cyclic                                                                         purified nitrate                                        triol       ester III ester VI                                  Example                                                                              R.sup.1                                                                              i.e. X =                                                                              n   (%)       (%)                                       ______________________________________                                         1     Ph     a       2   81        82*                                        2     Ph     a       4   86        84*                                        3     Ph     a       8   83        88*                                        4     Ph     b       2   92        81                                         5     Ph     b       4   91        78                                         6     Ph     b       8   87        83                                         7     Ph     c       2   93                                                   8     Ph     c       4   92                                                   9     Ph     c       8   91                                                  10     Ph     d       5   81        87                                        11     Ph     e       2   86        76˜                                 12     Ph     f       2             0                                         13     Ph     f       4             0                                         14     Ph     f       8             0                                         15     Ph     g       2             0                                         16     Ph     g       4             0                                         17     Ph     g       8             0                                         18     Bu     a       2   92        89*                                       19     Bu     a       4   93        82*                                       20     Bu     a       8   88        85*                                       21     Bu     b       2   93        85                                        22     Bu     b       4   98        94                                        23     Bu     b       8   94        86                                        24     Bu     c       2   87                                                  25     Bu     c       4   91                                                  26     Bu     c       8   89                                                  27     Bu     d       5   91        93                                        28     Bu     e       2   96        82˜                                 29     Bu     f       2             0                                         30     Bu     f       4             0                                         31     Bu     f       8             0                                         32     Bu     g       2             0                                         33     Bu     g       4             0                                         34     Bu     g       8             0                                         ______________________________________                                         Notes:                                                                        *a further one equivalent of N.sub.2 O.sub.5 was required to allow for        nitration of the third OH group                                               ˜a further two equivalents of N.sub.2 O.sub.5 were required to allo     for nitration of the phenyl ring                                         

                  TABLE 2                                                         ______________________________________                                                                             isolated yield                                                                        isolated yield                                                        of purified                                                                           of purified                                                           cyclic  nitrate                                                               ester V ester VII                        Example                                                                              R.sup.1                                                                             X.sup.1                                                                             X.sup.2                                                                           Y   Y.sup.1                                                                           Z     (%)     (%)                              ______________________________________                                        h      Bu    H     H   H   H   H     96      96                               i      Bu    Me    H   H   H   H     93      81                               j      Bu    Me    H   H   H   H     98      81                               k      Bu    Me    Me  H   H   H     94      84                               l      Bu    H     H   Me  Me  Me.sub.2 CH                                                                         96      68                               m      Bu    H     H   Pr  Me  H     99      79                               n      Bu    H     H   Bu  Et  H     98      89                               o      Bu    H     H   Et  Me  H     96      80                               p      Bu    H     H   Pr  Et  H     93      83                               ______________________________________                                    

What is claimed is:
 1. A process for the preparation of 1,2- and1,3-dinitrate esters from a corresponding polyol having a 1,2- or13-diol fragment that comprises the steps of:(a) preparing a cyclicboronate ester derivative of the polyol by treatment of the polyol withan alkyl or aryl boronic acid; (b) reacting the cyclic boronate esterderivative with dinitrogen pentoxide under anhydrous conditions in orderto form the corresponding dinitrate; and (c) separating the dinitrateester product from the boron-containing side product.
 2. The process asclaimed in claim 1 wherein the boronic acid is an alkyl boronic acid. 3.The process as claimed in claim 1 wherein the boronic acid is phenylboronic acid.
 4. The process as claimed in claim 1 wherein step (a) iscarried out at or that ambient temperature.
 5. The process as claimed inclaim 1 wherein step (b) is carried out using a solution of dinitrogenpentoxide in an organic solvent.
 6. The process as claimed in claim 5wherein the organic solvent is dichloromethane.
 7. The process asclaimed in claim 1 wherein step (b) is carried out at a temperature inthe range of -30° to +25° C.
 8. The process as claimed in claim 1 thatincludes the further step of recovering the boronic acid startingmaterial.